Our studies of cellular populations and of the role of individual proteins in effector functions of T-lymphocytes have obvious immunopharmacological implications since they identify the cell type and key proteins that should be targeted for efficient immunomodulation. A. Synthetic Peptides Inhibitors/Pseudosubstrates as Modulators of Cytotoxic Lymphocytes. We tested if it is possible to influence functional responses of intact cells using synthetic peptides which mimic pseudosubstrate sequences or inhibitory domains of known protein kinases. We found that some basic amino acid-containing synthetic peptide substrates of protein kinases strongly inhibited several cellular responses of CTL. Peptides which contain basic amino acids, but do not have substrate specificity determinants for protein kinase, were not inhibitory. The requirement for the relatively high concentration of peptides needed to demonstrate their effects may reflect their partial degradation by peptidases. The presented data support the model in which specific features of amino acid composition allow for the peptide internalization and interference with cellular functions. Future refinements of this approach include design of protease-resistant peptides and targeting protein kinases (e.g. PKA) using natural inhibitory protein amino acid sequences. B. Enhancement of Cytotoxic T Cells Functions by an Inhibitor of Serine/Threonine Phosphatase, Okadaic Acid. A specific and potent inhibitor of protein phosphatases 1 and 2A, okadaic acid (OA) at low concentrations enhanced, whereas at higher concentrations inhibited CTL responses as expected if protein phosphatases and protein dephosphorylation were indeed involved in the TCR-mediated signal transduction and effector responses of CTL. The biphasic character of the effects of OA on CTL-TC interactions suggests the existence of at least two functionally distinct phosphatases in CTL: an inhibitory phosphoprotein phosphatases that should be considered as a participant in the down-regulation of the cell-cell interactions between CTL and TC and yet another phosphatase that is needed for the TCR-mediated transmembrane signaling.